The present invention relates to a new process for the production of a 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamide compound selected from (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide, i.e. safinamide (Ia), (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide, i.e. ralfinamide (Ib),

the respective R-enantiomers (I′a) and (I′b), the respective racemic mixtures (Ia, I′a) and (Ib, I′b) and the salts thereof with pharmaceutically acceptable acids, (Ic), (Id), (I′c), (I′d) and their racemic mixtures (Ic, I′c) and (Id, I′d) in high yields and very high enantiomeric and chemical purity.
This method is also very useful for their production in large quantities. Safinamide (NW-1015, FCE-26743A, PNU-151774E) is a sodium channel blocker, a calcium channel modulator, a monoamino oxidase B (MAO-B) inhibitor, a glutamate release inhibitor and a dopamine metabolism modulator.
Safinamide is useful in the treatment of CNS disorders, in particular of epilepsy, Parkinson's disease, Alzheimer's disease, depression, restless legs syndrome and migraine (WO 90/14334, WO 2004/089353, WO 2005/102300 and WO 2004/062655).
Ralfinamide (NW-1029, FCE-26742A, PNU-0154339E) is a sodium channel blocker useful in the treatment of pain conditions, including chronic pain and neuropathic pain, migraine, bipolar disorders, depressions, cardiovascular, inflammatory, urogenital, metabolic and gastrointestinal disorders (WO 99/35125, WO 03/020273, WO 2004/062655, WO 2005/018627, WO 2005/070405, WO 2005/102300).
In particular, safinamide is specifically described in WO 90/14334. Safinamide, its R-enantiomer, their racemic mixture and their salts with pharmaceutically acceptable acids and the use thereof for the preparation of pharmaceutical compositions active as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agents are specifically claimed in WO 90/14334.
Ralfinamide is specifically described in WO 90/14334. Ralfinamide, its R-enantiomer, their racemic mixture and their salts with pharmaceutically acceptable acids and their use thereof for the preparation of pharmaceutical compositions active as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agent are comprised by the claims of WO 90/14334.
Moreover, the use as analgesics of safinamide, ralfinamide, the respective R-enantiomers, the respective racemic mixtures and their salts with pharmaceutically acceptable acids is claimed in WO 99/035125.
WO 2006/027052 A2 specifically discloses and claims the use of the single R-enantiomer of ralfinamide i.e., (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I′b), and its salts with pharmaceutically acceptable acids as a selective sodium and calcium channel modulator for the selective treatment of pathological affections wherein sodium or calcium channel mechanism(s) play(s) a pathological role, including pain, migraine, inflammatory processes affecting all body systems, disorders affecting skin and related tissue, disorders of the respiratory system, disorders of the immune and endocrinological systems, gastrointestinal, and urogenital disorders, wherein the therapeutical activity of said compound is substantially free from any MAO inhibitory side effect or exhibits significantly reduced MAO inhibitory side effect.
It has now been discovered that the large scale preparations of safinamide and ralfinamide according to the methods described in the prior art, contain two undesired impurities, i.e., respectively, (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (IIa) and (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide (IIb), and their salt, in particular the respective methanesulfonates (IIc) and (IId)

The same situation occurs with the preparation according the prior art methods for the R-enantiomers (I′a) and (I′b) of, respectively, safinamide and ralfinamide, the respective racemic mixtures (Ia, I′a) and (Ib, I′b), and the salts thereof with pharmaceutically acceptable acids, (I′c), (I′d) and the respective racemic mixtures (Ic, I′c) and (Id, I′d) in particular the methanesulfonates, which result to be contaminated by the respective R isomers (II′a), (II′b), (II′c), and (II′d) of the above identified impurities (IIa), (IIb), (IIc) and (lid) or the respective racemic mixtures (IIa, II′a), (IIb, II′b), (IIc, II′c) and (IId, II′d).
This fact is of particular relevance because it has been found that the impurities mentioned above show a very high toxicity against enzymes of the cytochrome P450 system.
Many of the drug candidates fail in clinical trials because of unforeseen effects on human metabolism, or toxicity, due to unwanted impurities and, therefore, the elimination of such impurities in early pre-clinical phase is important and strongly desirable.
At preclinical level, the “drugability” of new compounds can be assessed using a very well established battery of in vitro assays, such as interaction with drug-metabolizing enzymes, cytotoxicity, metabolic stability and profiling, membrane permeability, intrinsic clearance and human ether-a-go-go related gene (HERG) channel blockade etc.
The Cytochrome P450 (CYP 450) system is the principal enzyme system for the metabolism of lipophilic xenobiotics, including drugs, carcinogens, and environmental pollutants. CYP 450 is a heme-containing, membrane bound, multienzyme system that is present in many tissues but is present at the highest level in liver. In human liver, it is estimated that there are 15 to 20 different xenobiotic-metabolizing CYP 450 forms. So far, more than fourteen CYP gene families have been identified in mammals. Despite the existing high homology, extensive studies have revealed that each CYP family and subfamily has distinct roles in xenobiotic metabolism. Three CYP families CYP1, CYP2 and CYP3 account for about 70% of human hepatic microsomes CYPs with CYP3 accounting for approximately 30%. These CYPs are the major responsible for the metabolism of most marketed drugs.
The CYP1 family contains several members that include CYP1A1, CYP1A2 and CYP1B1 and they are involved in the metabolism of acetaminophen, clomipramine and imipramine.
The CYP2 family contains several subfamilies including CYP2A, CYP2B, CYP2C, CYP2D and CYP2E. The CYP2C subfamily contains at least seven members. CYP2C9 is responsible for the metabolism of ibuprofen, diclofenac, tolbutamide and torsemide. CYP2C19 is the major isoenzyme metabolizing diazepam and omeoprazole. CYP2D6 has been shown to be responsible for metabolizing over 30% of the drugs on the market, including, antidepressants and cardiovascular and anti-psychotic drugs.
In the CYP3 family, three isoforms have been identified in human liver. Human CYP3A4 has been recognized to be the most important isoform in drug metabolism. To date, metabolism catalyzed by CYP3A4 is the major elimination route for nearly 50% of marketed drugs.
Because of their importance in drug metabolism, both CYP3A4 and CYP2D6 are often involved in drug-drug interactions and several clinically used compounds have been identified as potent inhibitor of these CYP 450 isoforms such as ketoconazole, terfenadine, erythromycin, miconazole propanolol and quinidine, respectively. This imposes a clear limitation on the use of these drugs.
A further problem consists in sudden death as a side effect of the action of non antiarrhytmic drugs is a major pharmacological safety concern facing the pharmaceutical industry and the health regulatory authorities. In recent years, at least five blockbusters drugs (astemizole, sertindole, terfenadine, cisapride, grepafloxacin) have been withdrawn from the market due to reports of sudden death. In all cases, long QT syndrome (LQTS), an abnormality of cardiac muscle repolarization, that is characterized by the prolongation of the QT interval in the electrocardiogram, was implicated as a predisposing factor for “torsades de pointes”, a polymorphic ventricular tachycardia that can spontaneously degenerate to ventricular fibrillation and cause sudden death. Congenital LQTS can be traced back to several possible mutations resulting in defects in sodium channels, and two different potassium channels: the rapidly activating delayed rectifier (TKr) and the slowly activating delayed rectifier (IKs). Importantly, virtually every case of a prolonged duration of cardiac action potential related to drug exposure (acquired LQTS) can be traced to one specific mechanism: blockade of IKr current in the heart. This current, a major contributor to phase 3 repolarization at the end of QT interval, is conducted by tetrameric pores, with the individual subunits encoded by HERG. With blockade of HERG K+ channels widely regarded as the predominant cause of drug-induced QT prolongation, early detection of compounds with this undesirable side effect has become an important objective in the pharmaceutical industry.
Compounds with strong inhibition of drug-metabolizing enzymes, in particular CYP 450 enzymes, and HERG channel blocking properties have a high probability to be toxic and that their development has to be stopped at an early-stage.
As shown in the Table 1 the impurities (IIa), (IIb), (II′a), (II′b) and the respective racemates (IIa, II′a) and (IIb, II′b), as the methanesulfonate salt (IIc), (II′c), (IId), (II′d) and respective racemates (IIc, II′c) and (IId, II′d), strongly inhibit in the micro and submicromolar range CYP3A4, CYP2D6, CYP2C19, CYP2C9 and HERG currents and are highly cytotoxic, compared with safinamide methanesulfonate (Ic) and ralfinamide methanesulfonate (Id) with high purity degrees, containing less than 0.03% by weight of the above said impurities.
TABLE 1HERGCytotoxicityCYP3A4CYP2D6CYP2C19CYP2C9CYP1A2IC50,IC50,IC50,IC50,IC50,IC50,IC50,CompoundμMμMμMμMμMμMμMImpurity1.206.700.050.770.427.29>40(IIc)Impurity<18.810.090.150.154.9429.24(II′c)Impurity<111.840.060.310.175.5728.03(IIc, II′c)Safinamide27.0248.0>40>4023.85>40>40methane-sulfonate(Ic)Impurity2.6615.000.050.921.898.01>40(IId)Impurity<111.460.070.620.034.34>40(II′d)Impurity<114.340.061.190.034.9639.44(IId, II′d)Ralfinamide18.0>300>40>40>40>40>40methane-sulfonate(Id)
Table 2 shows comparative results (IC50) about the inhibition of the cytocrome CYP3A4 using samples of highly pure safinamide and ralfinamide methanesulfonate containing less than 0.03% by weight of the above said impurities in comparison with the same samples of highly pure safinamide and ralfinamide doped with 0.3% by weight of the impurity (IIc) and (IId), respectively.
When 0.3% by weight of the impurities (IIc) and (IId) are added to highly pure safinamide and ralfinamide methanesulfonate, a significant decrease in IC50 on CYP3A4 is observed in both cases meaning that the impurities contribute to a strong inhibition of the enzyme activity.
TABLE 2CYP3A4CompoundIC50, μMSafinamide>40methanesulfonateSafinamide18methanesulfonate plus0.3% (IIc) impurityRalfinamide>40methanesulfonateRalfinamide7.76methanesulfonate plus0.3% (IId) impurity
As shown in Table 3 the impurity (IIc) increases, starting from 3 mg/kg ip, the mortality in the mice Maximal Electroshock (MES) test without any pharmacological activity, i.e. protection from convulsions.
TABLE 3MES3 mg/kg ip10 mg/kg ip30 mg/kg ip%dead/%dead/%dead/CompoundprotectionliveprotectionliveprotectionliveSafinamide500/101000/101000/10methane-sulfonateImpurity IIc05/1004/1004/10
Table 4 reports that the impurity (IId), when given p.o. at 10 and 20 mg/kg, in the Maximal Electroshock test (MES) doesn't protect mice from convulsions if compared with the same doses of ralfinamide methanesulfonate.
TABLE 4MES10 mg/kg p.o.20 mg/kg p.o.CompoundProtection %Dead/liveDead/liveRalfinamide60%0/1090%0/10methanesulfonateImpurity (IId) 0%0/10 0%0/10
Based on all these data, the impurities (IIc), (II′c), (IId) and (II′d), and the respective racemic mixtures (IIc, II′c) and (IId, II′d) which are present in undesirable amount in safinamide, ralfinamide, their R-isomers and the respective racemic mixtures respectively, synthesized with the process described in WO 90/14334 and by Pevarello et al in J. Med. Chem, 1998, 41, 579-590, or in WO2006/027052, show in vitro some undesirable features, such as cellular toxicity, strong inhibition of some isoform of CYP 450, HERG channel blockade and no protective activity in an “in vivo” model of epilepsy.
One of the important aspects of CYP is the variation among different population groups. Variations in drug metabolism are of great importance in clinical studies. Considerable variation in the enzymatic activity of CYP3A4 and CYP2D6 has been demonstrated between different ethnic groups and even among different individuals in the same ethnic group. The difference in the CYP activity among individuals varies significantly, depending upon different isoenzymes. Changes in the CYP expression level of different individuals can cause variations in drug metabolism. More importantly, polymorphism can also result in CYP enzyme variants with lower or higher enzymatic activity that leads to variations in drug metabolism. CYP2D6 polymorphism is a well-studied topic in drug metabolism. In clinical studies, pronounced variations between individuals were first found in the metabolism of antihypertensive and antiepileptic drugs. Elimination of CYP2D6 metabolized drugs is slower in those individuals who carry defective CYP2D6 alleles. Individuals with slow metabolism are classified as poor metabolizers (PM), while catalytically competent individuals are called extensive metabolizers (EM): The incidence of the PM phenotype in population of different racial origin varies: approximately 5 to 10% of Caucasians are of the PM phenotype, but only 1% in Asian population. CYP2C19 is another important polymorphic isoform that has clinical implications.
Taken into account these observations, a compound that does not interfere with CYP450 isoforms (neither inhibition nor induction) has a very low risk for drug-drug interactions in clinical practice and can be simply and safely prescribed by physicians.
In particular, drugs that not interfere with the cytochromes of the CYP450 system are particularly indicated for the therapeutical treatment of individuals that are classified as poor metabolizers (PM) or for the therapeutical treatment of patients who are concomitantly assuming other drugs which are known to interfere with said cytochromes, such as ketoconazole, terfenadine, erythromycin, miconazole, propanolol and quinidine, and/or are known to have HERG channel blocking properties.
According to the common clinical practice, safinamide and ralfinamide methanesulfonates (Ic) and (Id) are usually administered to the patient in need thereof for a long period of time, subdivided in several daily dose. This is particularly the case of therapeutical applications wherein the disease to be treated is: Parkinson's disease, Alzheimer's disease and restless legs syndrome (for the use of safinamide) or chronic or neuropathic pain, cardiovascular or inflammatory disorders (for the use of ralfinamide). Although the daily dosage may vary according to the specific conditions and needs of the patients, the safinamide methanesulfonate daily dosage may usually range from 10 mg/day to 800 mg/day, while ralfinamide methanesulfonates daily dosage may usually range from 10 mg/day to 1 g/day. Under these conditions, and in consideration of the data reported above, it is highly advisable to keep the level of the impurities (IIa) and (IIb) or the salts thereof, in particular the methanesulfonate salts (IIc) and (IId) in the pharmaceutical dosage forms of safinamide and ralfinamide, or the salts thereof, as low as possible, in any case lower than 0.03%, preferably lower than 0.01% by weight with respect to the amount of, respectively, safinamide and ralfinamide, or the salts thereof, in particular the methanesulfonate salts.
The same considerations apply to the R-enantiomers of safinamide and ralfinamide (I′a) and (I′b), the respective racemic mixture (Ia, I′a) and (Ib, I′b) and the salts thereof with pharmaceutically acceptable acids with regards to the respective impurities (II′a), (II′b), the respective racemic mixtures (IIa, II′a) and (IIb, II′b) and the salts thereof with pharmaceutically acceptable acids.
Investigations and experimental studies carried out by the inventors have shown that safinamide, ralfinamide, the respective R-enantiomers, the respective racemic mixtures or the salts thereof with pharmaceutically acceptable acids, when prepared according to the prior art methods contain an amount of the respective impurities (IIa), (IIb), their R-enatniomers (IIa) and (II′b), the respective racemic mixtures (IIa, II′a) and (IIb, II′b), or the salts thereof with pharmaceutically acceptable acids, (such as (IIc), (IId), (II′c) and (IId) or the respective racemic mixtures (IIc, II′c) and (IId, II′d)) that are higher than 0.03% by weight. Therefore, the above said products are unsuitable for wide and safe therapeutical applications. In particular, pharmaceutical preparations containing safinamide, ralfinamide, the respective R-enantiomer (I′a) or (I′b), the respective racemic mixture (Ia, I′a) and (Ib, I′b) or the salt thereof with pharmaceutically acceptable acids, wherein the content of the respective impurities (IIa), (IIb), (IIa), (II′b), their racemic mixture (IIa, II′a) and (IIb, II′b), or the salts thereof with pharmaceutically acceptable acids is not lower than 0.03%, preferably than 0.01%, by weight with respect to the above said therapeutically active substances, are not suitable for use as medicaments in particular groups of patients as described above.
In particular, pharmaceutical preparations containing safinamide, ralfinamide, the respective R-enantiomers (I′a) or (I′b) or the respective racemic mixtures (Ia, I′a) and (Ib, I′b), or the salt thereof with pharmaceutically acceptable acids, wherein the content of the respective impurities (IIa), (IIb), (IIa), (II′b), the respective racemic mixtures (IIa, II′a) and (IIb, II′b), or the salts thereof with pharmaceutically acceptable acids is not lower than 0.03%, preferably than 0.01%, by weight with respect to the above said active substances, are not suitable for use in the therapeutical treatment of a wide population of patients including those individuals that are classified as poor metabolizers (PM) or who are concomitantly assuming other drugs that are known to interfere with the cytochromes of the CYP 450 system.
In this specification and claims the values of the above indicated limits, unless as otherwise specified, are to be intended as expressing the percent ratio by weight of the “active substances”, i.e., the effective content of the toxicologically active impurity (IIa), (IIb), (II′a), (II′b), or the respective racemic mixtures (IIa, II′a) and (IIb, II′b) measured with respect to the effective content of the therapeutically active substance (Ia), (Ib), (I′a), (I′b) or the respective racemic mixtures (IIa, II′a) and (IIb, II′b).
The expressions such as “high purity”, “high purity degree”, “high chemical purity”, “highly pure” etc, when referred to safinamide, ralfinamide the respective R-enantiomers, the respective racemic mixtures, or the salts thereof with pharmaceutically acceptable acids, in this description and claims identify products containing not less than 98.5 percent (evaluated as area percent by HPLC methods) of safinamide (Ia), ralfinamide (Ib), the respective R-enantiomers (I′a) and (I′b), the respective racemic mixtures (Ia, I′a) and (Ib, I′b) or the salts thereof with pharmaceutically acceptable acids wherein the content of the respective impurity (IIa), (IIb), (IIa), (II′b), the respective racemic mixtures (IIa, II′a) and (IIb, II′b), or the salts thereof with pharmaceutically acceptable acids is lower than 0.03 percent, preferably lower than 0.01 percent, by weight (referred to the “active substances”) determined by HPLC methods.
Other impurities, barely detectable, derive from the very small quantities of benzyl, 2- and 4-fluorobenzyl chloride and of 3- and 4-fluorobenzyl chloride which are contained in the commercially available 3-fluorobenzyl chloride and 2-fluorobenzyl chloride respectively, used for the synthesis of 4-(3-fluorobenzyloxy)benzaldehyde (IVa) and 4-(2-fluorobenzyloxy)benzaldehyde (IVb) intermediates for the preparation of, respectively, compounds (Ia), (Ib), (I′a), (I′b) (Ia, I′a) and (Ib, I′b) and their salts with pharmaceutically acceptable acids.
Analogously, the above mentioned terms, “high purity”, “high purity degree”, “high chemical purity”, “highly pure”, when referred to the 4-(3- or 2-fluorobenzyloxy)benzaldehyde intermediates (IVa) and (IVb), identify products containing not less than 98.5 percent (evaluated as area percent by GC methods) of each of the above named compounds and wherein the content of the respective di-benzylated impurity (VIa) or (VIb) is lower than 0.03 percent, preferably lower than 0.01 percent by weight (evaluated by GC methods).
The process described in this invention, by strongly reducing the impurities, provides products with high chemical purity and safer biological profile.
According to the process described in the present invention safinamide, ralfinamide, the respective R-enantiomers (I′a) and (I′b), the respective racemic mixtures (Ia, I′a) and (Ib, I′b) and the salts thereof with pharmaceutically acceptable acids, in particular with methanesulfonic acid, are obtained with high yields and high purity where the content of the respective impurities (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzylamino]propanamide (IIa), (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzylamino]propanamide (IIb), the respective R-enantiomers (II′a) and (II′b), the respective racemic mixtures (IIa, II′a) and (IIb, II′b) and the salt thereof with pharmaceutically acceptable acids, in particular with methanesulfonic acid (generically named “dibenzyl derivatives”) is lower than 0.03%, preferably than 0.01% (by weight), referred to the “active substances”.
A further object of this invention is to provide safinamide, ralfinamide, the respective R-enantiomers, the respective racemic mixtures or the salts thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, with a high purity degree, in particular with a content of the respective dibenzyl derivatives of the formula (IIa), (IIb) (II′a), (II′b), their racemic mixtures (IIa, II′a) and (IIb, II′b), or the salts thereof with a pharmaceutically acceptable acid, e.g. the methanesulfonic acid, lower than 0.03%, preferably lower than 0.01% by weight (referred to the “active substances”), which is suitable for their safe use as medicaments.
Another object of this invention is to provide pharmaceutical formulations comprising safinamide, ralfinamide, the respective R-enantiomers (I′a) and (I′b), the respective racemic mixtures (Ia, I′a) and (Ib, I′b) or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, as the active agents wherein the content of the respective dibenzyl derivatives (IIa), (IIb), their R-enantiomers (II′a) and (II′b), the respective racemic mixtures (IIa, II′a) and (IIb, II′b) or the salt thereof with a pharmaceutically acceptable acid, e.g. methanesulfonic acid, is lower than 0.03%, preferably lower than 0.01% by weight (referred to the “active substances”).
More particularly, according to a preferred embodiment of this invention, the process herein disclosed allows the production of a medicament containing highly pure (i) safinamide, its R-enantiomer (I′a) their racemic mixture or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, or (ii) ralfinamide, its R-enantiomer (I′b), their racemic mixture (IIa, II′a) and (IIb, II′b) or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, for the treatment of, respectively, (i) epilepsy, Parkinson's disease, Alzheimer's disease, depression, restless legs syndrome pain and migraine, or (ii) pain conditions including chronic and neuropathic pain, migraine, bipolar disorders, depressions, cardiovascular, inflammatory, urogenital, metabolic and gastrointestinal disorders, under conditions that are not interfering with the cytochromes of the CYP450 system, in particular CYP3A4, CYP2D6, CYP2C19, CYP2C9 and do not exhibit HERG channel blocking properties.
Moreover, according to a further preferred embodiment of this invention, the process herein disclosed allows the preparation of a medicament containing highly pure ralfinamide single R-enantiomer, or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, for the selective (i.e., where the therapeutical activity of the active substance which is administered to the patient is substantially free from any MAO inhibitory side effect or exhibits significantly reduced MAO inhibitory side effect) treatment of the pathological affections where sodium and/or calcium channel mechanism(s) play(s) a pathological role that are identified in WO 2006/027052 A2, such as, pain, migraine, inflammatory processes affecting all body systems, disorders affecting skin and related tissues, disorders of the respiratory system, disorders of the immune and endocrinological system, gastrointestinal, and urogenital disorders, under conditions that are not interfering with the cytochromes of the CYP450 system, in particular CYP3A4, CYP2D6, CYP2C19, CYP2C9 and do not exhibit HERG channel blocking properties.
Therefore, the process of this invention allows the manufacture of pharmaceutical formulations containing safinamide, its R-enantiomer (I′a), ralfinamide, its R-enantiomer (I′b), the respective racemic mixtures, (Ia, I′a) and (Ib, I′b) or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, which are suitable for the treatment of the above mentioned disorders in patients that are classified as poor metabolizers (PM) or for the therapeutical treatment of patients who are concomitantly assuming other drugs which are known to interfere with the cytochromes of the CYP450 system and/or are known to have HERG channel blocking properties.
All these new pharmaceutical formulations were neither suggested nor achievable by applying the pharmaco-toxicological knowledge regarding safinamide and ralfinamide nor by using these active agents prepared according to the methods available in the state of the art. The above said pharmaceutical formulations may optionally comprise one or more additional active agents, besides safinamide, ralfinamide, the resptective R-enantiomers, the respective racemic mixtures or the salts thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, having the above described high purity degree. For instance, a new pharmaceutical formulation useful for the adjunctive treatment of Parkinson's disease or restless legs syndrome may comprise one or more adjunctive Parkinson's disease active agent(s) such as those described in WO 2004/089353 and WO 2005/102300, preferably a dopamine agonist and/or levodopa and/or a catechol-O-methyltransferase (COMT) inhibitor, in addition to safinamide, its R-enantiomer, their racemic mixture, or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, obtained according to the process of this invention and having the above said high purity degree.
As a further example, a new pharmaceutical formulation according to this invention useful for the treatment of pain conditions, including chronic pain and neuropathic pain, and migraine may optionally contain a further active agent such as gabapentin and pregabalin, or a pharmaceutically acceptable salt thereof as described in EP 1423168, in addition to ralfinamide, its R-enantiomer, their racemic mixture, or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, obtained according to the process of this invention and having the above said high purity degree.
Similarly, a new pharmaceutical formulation according to this invention, useful as a medicaments selectively active as sodium and/or calcium channel modulator for the selective treatment of pathological affections where sodium and/or calcium channel mechanism(s) play(s) a pathological role according to WO 2006/027052 A2, such as, pain, migraine, inflammatory processes affecting all body systems, disorders affecting skin and related tissues, disorders of the respiratory system, disorders of the immune and endocrinological system, gastrointestinal, and urogenital disorders may optionally contain a further active agent. For instance, a pharmaceutical formulation for treating pain conditions may contain gabapentin or a gabapentin related agent in addition to the single R-enantiomer of ralfinamide (I′b) or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, obtained according to the process of this invention and having the above said high purity degree.
The pharmaceutical compositions containing high purity degree safinamide, ralfinamide, the respective R-enantiomers, the respective racemic mixtures, or the salts thereof with pharmaceutically acceptable acids according this invention can be prepared by conventional procedures known in the art, for instance by mixing the active compounds with pharmaceutically, therapeutically inert organic and/or inorganic carrier materials. The compositions of the invention can be in liquid form, e.g. in the form of a solution, suspension, emulsion; or in solid form, e.g. tablets, troches, capsules, patches.
Suitable pharmaceutically, therapeutically inert organic and/or inorganic carrier materials useful in the preparation of the composition of the present invention include, for example, water, gelatine, arabic gum, lactose, starch, cellulose, magnesium steareate, talc, vegetable oils, polyalkyleneglycols, cyclodextrins and the like. The pharmaceutical compositions of the invention can be sterilized and may contain, besides the active ingredient(s), further components well known to the skilled in the art, such as, for example, preservatives, stabilizers, wetting or emulsifying agents, e.g. paraffin oil, mannide monooleate, salts to adjust osmotic pressure, buffers and the like.
A further object of this invention is to provide a method for treating CNS disorders, in particular epilepsy, Parkinson's disease, Alzheimer's disease and restless legs syndrome, which method comprises administering to a patient in need thereof an effective amount of high purity degree safinamide, its R-enantiomer, their racemic mixture, or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, having a content of the respective dibenzyl derivatives (IIa), (IIa), their racemic mixture (IIa, II′a) or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, lower than 0.03%, preferably lower than 0.01% by weight (referred to the “active substance”). Said method includes treating Parkinson's disease or restless legs syndrome by administering to a patient in need thereof an effective amount of the high purity degree safinamide its R-enantiomers (I′a), their racemic mixture (Ia, I′a) or a salt thereof, as described above, optionally in conjunction with one or more Parkinson's disease active agent(s) as described in WO 2004/089353, such as, for instance, a dopamine agonist and/or levodopa and/or a catechol-O-methyltransferase (COMT) inhibitor.
Moreover, a further object of this invention is to provide a method for treating pain conditions including chronic pain and neuropathic pain, migraine, bipolar disorders, depressions, cardiovascular, inflammatory, urogenital, metabolic and gastrointestinal disorders which method comprises administering to a patient in need thereof an effective amount of high purity degree of ralfinamide, its R-enantiomer, their racemic mixture, or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, having a content of dibenzyl derivative (IIb), (II′b), their racemic mixture (IIb, II′b), or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, lower than 0.03%, preferably lower than 0.01% by weight (referred to the “active substance”). The above said method includes treatment of pain conditions, comprising chronic pain and neuropathic pain, and migraine with high purity degree ralfinamide, its R-enantiomer, their racemic mixture or a salt thereof with a pharmaceutically acceptable acid, preferably methanesulfonic acid, optionally in conjuction with gabapentin or pregabalin.
Additionally, a further object of this invention is to provide a method for the selective treatment of a pathological affection wherein sodium or calcium channel mechanism(s) play(s) a pathological role, including pain, migraine, inflammatory processes affecting all body systems, disorders affecting skin and related tissues, disorders of the respiratory system, disorders of the immune and endocrinological systems, gastrointestinal, and urogenital disorders, wherein the therapeutical activity of said compound is substantially free from any MAO inhibitory side effect or exhibits significantly reduced MAO inhibitory side effect, which method comprises administering to a patient in need thereof a therapeutically effective amount of ralfinamide single R-enantiomer (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide, or a salt thereof with a pharmaceutically acceptable acid, preferably a salt with methanesulfonic acid, which has a content of impurity (R)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzylamino]propanamide (II′b), or a salt thereof with a pharmaceutically acceptable acid, preferably with methenesulfonic acid, lower than 0.03%, preferably lower than 0.01% (by weight), optionally in conjunction with a further active agent, for instance in the case of the treatment of pain conditions, gabapentin or a gabapentin related substance.
The above mentioned methods of treatment are particularly useful in patients affected by the diseases listed above who are classified as poor metabolizers (PM) or who are concomitantly assuming other drugs which are known to interfere with the cytochromes of the CYP 450 system. In this description and claims the terms “treatment” or “treating” include prevention, alleviation and cure.